Cerebrum

Alzheimer’s disease, with its irreversible cognitive decline and its increase in populations growing older, tends to dominate public anxiety about dementia. A different cause of dementia, equally devastating, often strikes those in their 50s and can have very different manifestations. In the case of this disorder, frontotemporal dementia, there is another and much more heartening difference; it appears that effective treatment could be coming. Might an advancement here lead the way for other neurodegenerative illnesses?

I’m having lunch in a diner. It’s the political campaign season, so at ﬁrst I’m not especially surprised when an enthusiastic man boisterously announces his entry. He tours the room like a brass band and introduces himself, clapping my fellow patrons on the back, shaking hands eagerly, and making jocular sexual comments, winking, smiling. Sitting down, he continues to joke, more loudly, now, almost aggressively, to the chagrin of the people already seated at that table. He begins eating food from his neighbor’s plate, enthusiastically shoveling the food into his mouth while providing a running commentary and ignoring the bewilderment of his new-found luncheon companions. Without warning, he bolts up, his chair crashing to the ground. He hollers a few words about the temperature of the food and stomps out the door.

A bizarre parody of modern-day political campaigning? No. I had, instead, witnessed behavior characteristic of a neurodegenerative condition called frontotemporal dementia or FTD.

Other people with FTD may exhibit different but equally startling behavior. For some, it is as if a page has been ripped from their mental dictionary. At unexpected points in a conversation, one person may pause after a familiar word is mentioned and intone with a look of desperation, “ ‘Chair?’ ‘Chair?’ I know I’ve heard that word...What is ‘chair?’ ” Another may look out the window as a deer runs by and wonder, “What is that? I should know what that is!” Still others appear to conduct their day-to-day business independently and unremarkably, shopping for groceries, balancing their checkbooks, attending concerts. Yet, on closer examination, the effort involved in speaking has become so overwhelming for them that they are virtually mute. All of these disorders of language can be manifestations of FTD.

When we think of cognitive decline and dementia in middle-aged and older adults, we most frequently think of Alzheimer’s disease. But in people younger than 65, FTD is as common as Alzheimer’s, and may account for 12 to 15 percent of all neurodegenerative disorders affecting cognitive ability. The prime targets of the disease—the brain’s frontal and temporal lobes—give it its name.

Although the disease has shown up as early as age 21 and as late as 85, FTD typically begins in people in their late 50s. Striking at an age when people are at the height of their careers and may be key decision makers, the disease has a shattering effect not only on the victim but also on family members and society. For spouses, and for children still living at home, the asocial behavior and communication limits of FTD can range from frustrating to embarrassing to devastating.

For many years, most of what we knew about FTD came from observing the behavior of its victims. Now, brain research has uncovered the critical role of a protein called tau, which is metabolized abnormally in the brains of people with FTD. As a result, we may soon have treatments that target the disease’s speciﬁc neurobiologic abnormality. In developing and applying these treatments, now proven viable in animal models, it will be essential to be able to distinguish FTD from more common dementias, such as Alzheimer’s, and other conditions that cause cognitive decline in adults—neurodegenerative diseases such as Lewy body disease or Creutzfeldt-Jakob disease, certain nutritional deﬁciencies, endocrinologic malfunctions, and infectious diseases.

DETERIORATING LANGUAGE AND BEHAVIOR

FTD typically manifests either as a disorder of social behavior and personality or as a progressive inability to understand and use speech (aphasia). We see these two faces of the disease even in the earliest descriptions. Credit for the ﬁrst published description, in 1892, goes to Arnold Pick, a keen observer of human behavior practicing in Prague who reported the case of a respected and proper housewife whose behavior gradually became socially inappropriate. She joked loudly and demonstrated inappropriate sexual behavior, apparently with little insight into how she was acting or the distress she was causing others. Her speech subsequently became effortful but otherwise retained its meaningfulness. Pick also reported on a second patient, whose speech was ﬂuent but often without meaningful content. Over the years, similar cases appeared in the French and German medical literature.

Aphasia associated with FTD is a “central” disorder; the language impairment is not explainable by deafness, blindness, or motor weakness. The form of aphasia associated with ﬂuent speech is known as “semantic dementia.” The person has difﬁculty comprehending single words and the concepts associated with them—even familiar single words. The earliest manifestation of semantic dementia is an isolated naming difﬁculty, or anomia. The person may attempt to describe something by talking around the target word and may substitute vaguer terms: for example, using “animal” to name a cat, a robin, a frog, or a mosquito. The person also resorts to excessive use of words such as “stuff” and “thing.”

Eventually, difﬁculty with comprehending words involves larger portions of the vocabulary. A person with semantic dementia can deﬁne a lost word only in the vaguest way. These problems are evident in both conversation and writing. Difﬁculty with reading may be particularly pronounced for words that cannot be sounded out, such as “yacht” or “choir.” Similarly, the person with FTD has more difﬁculty spelling words when the letter-sound correspondence is not straight forward. Speech remains relatively ﬂuent even as the meaningful content of the speech decreases; sentences are grammatical and comprehension of grammar appears to be maintained. But ultimately these patients lose other aspects of the concepts underlying a word. For example, not only is the word “hammer” lost, but so is the ability to recognize a hammer or use a hammer correctly.

Another common FTD language difﬁculty is called “progressive nonﬂuent aphasia” (PNFA). Here, comprehension and expression of single words remain relatively good, although there may be some difﬁculty in naming things. The big problem is speech ﬂuency. Fluency depends on access to grammatical forms, such as the small words with which we stitch together a sentence. People with PNFA may repeat a sentence like “Jane was kicked by Fred” as “Jane kick Fred.” Meaning can be distorted because the relationships between the words in the sentence are lost. As grammar falls apart, speech becomes disjointed and effortful, and speaking and writing consists largely of slowly produced content words. The person’s comprehension is similarly affected and for the same reasons. The sentence “Jane was kicked by Fred,” if perceived as “Jane kick Fred,” would be understood as a girl kicking a boy.

Still another related form of progressive aphasia primarily affects the physical production of speech and causes a progressive form of dysarthria (poorly articulated speech). People with progressive dysarthria comprehend what is said to them and have no difﬁculty in reading and writing. Their speech is grammatical but garbled. Their facial muscles and tongues are not inherently weak, but the coordination necessary to produce speech appears to be impaired.

A DISRUPTION IN PERSONALITY

In other people with FTD, the primary effects are on the emotions, personality, and behavior. These people seem insensitive to ordinary social norms. At ﬁrst, they make only occasional odd or inappropriate statements or voice unusual opinions. Soon, however, it becomes clear that these are not isolated incidents. As FTD progresses, people may blurt out comments without any sensitivity or consideration of context. Their loss of social graces and frank callousness may be entirely at odds with their earlier personality. They are apparently clueless about the intentions of others and entirely self-centered, seemingly lacking empathy for the difﬁculties of others. It seems to make no difference whether they are interacting with strangers or close family members.

The stark changes in personality can go still further. People with FTD can be hypersexual, having promiscuous sexual encounters with strangers or making inappropriate sexual demands of spouses. Examples of subtler manifestations of hypersexual behavior can be a fetish associated with a movie star, a focus on sexual jokes, or inappropriate sexual comments. Another form of disinhibited behavior is an inappropriate attraction to small shiny objects or to ﬁre, so that the person may shoplift or pocket attractive objects from the homes of friends or start ﬁres.

Sudden, unexpected outbursts of angry behavior can be an aspect of FTD, and, in rare cases, a person becomes physically and emotionally violent with minimal or even imaginary provocation. Regardless of the perceived slight, they can produce a verbal tirade that sometimes is difﬁcult to quell, because they do not appear to understand attempts to explain the situation or calm their anger.

The catalog of possible behaviors in FTD is long, because we are dealing with the gradual deterioration of whole regions of the brain that direct our thoughts, feelings, and actions. We are witnessing the disintegration of an entire, complex adult personality, with all its carefully acquired abilities. Some people with FTD exhibit what we call “hyperoral” behavior, ranging from the disinhibited consumption of large volumes of food to oral exploration of inedible objects. Obsessive changes in food preferences can be involved, and the person’s diet can become restricted to highly idiosyncratic choices, such as nothing but chocolate-covered donuts. Not surprisingly, these changes in eating patterns can cause radical gains or losses of weight.

Changes in mood or motivation are also common. The person with FTD may appear to be profoundly apathetic, failing to initiate the simplest behaviors. A husband’s or wife’s urging to get involved with a previously enjoyed hobby can yield no response. The person may have little or no concern even with going to the toilet, with predictable consequences.

We have been discussing speciﬁcally social manifestations, but certainly there is overlap here with cognitive difﬁculty caused by limitation in what are called the brain’s “executive” operations. These include selective attention, the ability to demonstrate dual-tasking, mental organization, planning skills, and inhibition of certain behavior. All may be compromised in people with FTD. They are easily distracted and can have trouble refocusing their attention. With little control over attention and inhibition, they can repeat the same activities, which is known as perseveration. For example, a person may keep repeating uncontrollably the same phrase, even though it is no longer meaningful (“I love Timmy”) or repeat the same gesture (such as hair combing). Another form of repetition is echolalia, mindlessly echoing a phrase that has just been uttered. Patients also can become “environmentally dependent” or “perceptually bound,” thoughtlessly incorporating objects in the environment into ongoing activities. Seeing reading glasses on a table, they may put them on over a pair of glasses they are already wearing.

Dual-tasking, mental organization, and planning all require us to alternate between cognitive and physical activity in ﬂexible, purposeful ways. When this ability succumbs to FTD, people can perform only simple tasks. Each thought and action seems to be initiated anew so that people with FTD can appear to be sluggish and slow. They need considerable guidance, even for familiar daily activities like bathing, although, with close guidance, the person can get through even complex activities.

Working memory—the ability to manipulate a small amount of information held in mind brieﬂy—also deteriorates in FTD. Working memory is involved in many activities, such as following and understanding a conversation or a movie, so limitations here can make the person seem disjointed in conversation. Poor working memory can reduce enjoyment of activities such as watching television or reading.

THE PROTEIN CALLED TAU

What is damaging the frontal and temporal lobes of people with FTD, causing these devastating changes in language, behavior, or both? By carefully examining the brains of people who died of FTD, scientists discovered that, in all forms of FTD, the most prominent feature was an abnormal metabolism of the protein tau. The condition is termed “tauopathy.”

The tau protein is an essential building block of the cytoskeleton of brain cells, or neurons. The cytoskeleton maintains the unique shape of the neuron and its long axon projecting from the cell body to the synaptic space adjacent to another neuron. The axon allows communication from one neuron to the next, producing networks of neurons that sustain our cognitive and social functioning. The cytoskeleton is also crucial in delivering substances down the axon to where they are needed at its active distant terminus. In FTD, tau function can be interrupted in several ways. For example, there may be an imbalance of the various forms of tau that are normally found in the brain; tau may become chemically altered at crucial points that impair its function; or it may become profoundly depleted in the brain.

The instructions for creating all proteins are in our genes. A gene on chromosome 17 codes for the tau protein. About 6 percent of people with FTD have a mutation of that gene, called the tau gene. Because fully one third of people with FTD have a strong family history of the disease, it is likely that other genes we have not yet identiﬁed also contribute to FTD’s occurrence. Mutations of the tau gene appear to cluster in the region of the gene where the splicing for the various forms of the tau protein is controlled, and where a structure is coded that is thought to play a crucial role in the functioning of tau.

Researchers initially used postmortem evaluations of the brain to ascertain the prevalence of tau in people with FTD. Now, it is possible to quantify tau in living patients by examining the cerebrospinal ﬂuid that bathes the brain and spinal cord. Several studies have identiﬁed a wide range of tau concentrations in the cerebrospinal ﬂuid, but, strangely, about one third of people with FTD have a concentration of tau so low that it cannot be detected.

Scientists are trying to ﬁnd out whether this low concentration in the cerebrospinal ﬂuid results from too much tau accumulation in the brain or from such profound depletion of tau that there is little left to diffuse from the brain into the cerebrospinal ﬂuid.

Scientists are trying to ﬁnd out whether this low concentration in the cerebrospinal ﬂuid results from too much tau accumulation in the brain or from such profound depletion of tau that there is little left to diffuse from the brain into the cerebrospinal ﬂuid. Whatever the answer, low tau concentrations appear to be an important marker, or indication, for FTD. By using tau concentrations along with analysis of other proteins in the cerebrospinal ﬂuid to distinguish between FTD and Alzheimer’s disease, one group of researchers was recently able to match the clinical diagnosis of the two diseases in more than 85 percent of the cases they studied.

Although we do not yet know just why this tau disorder particularly affects the frontal and temporal lobes of the brain, neuroimaging provides another objective means of diagnosing FTD. With the advent of high-quality magnetic resonance imaging (MRI), we can measure areas of signiﬁcant frontal and temporal cortical atrophy in people with FTD. Comparing these images with those of people suffering from other neurodegenerative disorders, such as Alzheimer’s, has helped scientists identify several distinct patterns of damage that help in diagnosing FTD. Unfortunately, the accuracy of a diagnosis based only on neuroimaging is limited because normal brain anatomy varies widely from person to person. A series of neuro-imaging studies of the same person taken over a period of months or years, giving us a baseline, is particularly useful in spotting the progressive cortical atrophy that characterizes FTD.

Advances like these in imaging and biochemistry have inspired attempts to image the protein abnormalities themselves in the brains of patients suffering from FTD and other neurodegenerative diseases. The more we understand the neurobiology of FTD, the more accurate is our diagnosis. Knowledge is critical also in developing new treatments to stem the downward spiral of the disease.

THE TRAJECTORY OF DECLINE

FTD is a progressive neurodegenerative condition; patients worsen over time in the cognitive domains where they have difﬁculty. But the trajectory of decline is not linear. During an initial mild stage, there can be a relatively prolonged period of subtle and insidious change that involves few fundamental problems. The changes that do emerge are typically restricted to the type of difﬁculty that brought the patient to medical attention in the ﬁrst place. For example, people with semantic dementia may have a gradual decline in single word comprehension and vocabulary, and people with progressive nonﬂuent aphasia can have increasing difﬁculty with grammatical comprehension and expression. People who have a disorder of personality and social behavior can have gradually worsening behavior. Because FTD is progressive, however, observing no change at all over a prolonged period should raise questions about a diagnosis of FTD.

The second or moderate stage of FTD is shorter and marked by the more rapid emergence of changes. Qualitatively different kinds of language, cognitive, and behavioral changes can appear. For example, a patient who initially exhibited semantic dementia can begin having difﬁculty with grammatical aspects of language. A person with progressive non-ﬂuent aphasia can begin to demonstrate personality and social changes. Someone with a disorder of social behavior can begin to demonstrate limitations in performing executive skills. People in the moderate stage of FTD become increasingly dependent on others and require verbal guidance and prompting for key activities of daily living, such as grooming, bathing, and dressing, that they previously performed independently. By the time FTD reaches its severe stage, people depend on others for virtually all activities of daily living, even basic mobility. Language, cognitive, and personality disorders can be broad.

The rate of decline and the ﬁnal prognosis for people with FTD are affected by a combination of biological and environmental factors, including other illnesses. By the time people are at the severe stage of the disease and are completely dependent on others for daily needs, the quality of the nursing care has an enormous effect on morbidity and mortality. Difﬁculty with eating independently can result in aspiration of food into the lungs because of such factors as poor control of the oral musculature and inattention. Changes in gait stability and poor postural adjustment can result in frequent falls. Apathetic patients with reduced mobility, lack of motivation, and limited ability to plan may not adjust their posture for a long time, so nursing staff members need to help them make frequent postural adjustments to avoid skin ulcers or bedsores. Incontinence, often an early result of apathy and poor social insight, can lead to urinary tract infections.

TOWARD REAL HOPE

As populations in many countries age and the frequency of neurodegenerative diseases such as FTD correspondingly increases, we are approaching the treatment of these conditions with a new sense of urgency. Happily, it is now possible for us to imagine the availability of effective treatments. Researchers have already demonstrated the viability of an approach to the treatment of abnormal tau in an animal model of FTD and are actively pursuing how this might be applied in humans. Such hoped-for treatments will deal not only with the symptoms of the disease, as important as that is, but also target the underlying neurobiology so that the course of the disease can actually be changed. A condition such as FTD will thus become a treatable cause of dementia.

The consequences of developing a treatment for FTD that focuses on tau is important for other neurodegenerative conditions, as well. For example, abnormalities of tau metabolism are also evident in Alzheimer’s disease. Improved understanding of the molecular biology of FTD and the role of tau has made it possible to develop animal models in which researchers can rapidly examine potential treatments, assess their safety and efﬁcacy, and move the most promising treatments on to human clinical trials. Potential therapies can focus on the abnormalities associated with the metabolism of tau or the breakdown of tau functioning in the neuronal cytoskeleton. Evidence exists that antioxidants such as Vitamin E may be able to stabilize tau.

At present, management of FTD still focuses on treating symptoms. And, unfortunately, there are few systematic clinical trials of medications or rigorous studies of behavioral interventions. Symptomatic treatment includes supplementing speciﬁc neurotransmitters such as serotonin.

Medications developed for other conditions such as Alzheimer’s disease, Parkinson’s disease, and depression can help slow the progression of FTD, but they must be used under the guidance of a knowledgeable physician, because some of these medications can worsen symptoms in some patients. Other treatments are directed at speciﬁc complaints, such as the management of agitation, delusions, depression, fatigue, anxiety, and hypersexual behavior.

Intervening to change behavior, including encouraging more physical and mental activity, can help. Some evidence suggests that the two are synergistic; daily physical and mental activity help more than either alone. Because people with FTD commonly have trouble organizing, a structured environment can help them carry out more activities independently. A chart that schedules their activities hourly throughout the day can often ease the burden of planning and motivation.

Although FTD is neither as common or as well known as other neurodegenerative diseases such as Alzheimer’s, its effect is great because of the family and societal responsibilities frequently held by people in their 50s, when the disease most often begins to take its terrible toll. Dementia is among the most frightening things that can happen to our brains or the brains of those we care about. But at last there is hope that we are on the cusp not only of accurate diagnosis but also of effective treatment, even a cure, for FTD.

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Bill Glovin, editor Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board Joseph T. Coyle, M.D., Harvard Medical School Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital Robert Malenka, M.D., Ph.D., Stanford University School of Medicine Bruce S. McEwen, Ph.D., The Rockefeller University Donald Price, M.D., The Johns Hopkins University School of Medicine